Research in our laboratory is focused on two major topics (1) the mechanisms by which viruses avoid the interferon (IFN)-mediated antiviral response, and (2) the role of translational regulatory mechanisms in the control of cell growth. These two interests are interconnected through our interest in the IFN-induced protein kinase, PKR, which plays a major role in mediating the antiviral and antiproliferative properties of IFN. Activation of PKR by viral RNA causes the virus-infected cell to shut down the production of new proteins, thereby limiting viral replication. Not surprisingly, many viruses have evolved strategies to repress PKR activity. Most recently we have shown that PKR is inhibited by the hepatitis C virus (HCV)-encoded NS5A protein, suggesting a possible mechanism used by HCV to avoid the antiviral effects of IFN, the only currently available treatment for HCV infection. In influenza virus-infected cells, we have shown that PKR activity is inhibited by a cellular protein, termed P58IPK. The overexpression of P58IPK in normal cells results in a transformed phenotype, which we recently found to be mediated by inhibition of PKR activity and by a PKR-independent mechanism. P58IPK itself was shown to be regulated by two proteins, a novel protein (designated P52rIPK) and heat shock protein 40, suggesting that P58IPK is part of a general stress-response pathway. We have examined the effects of IFN on human immunodeficiency virus (HIV) and simian immunodeficiency virus replication and have demonstrated that IFN inhibits these viruses by unique mechanisms, revealing differences in viral replication strategies. Finally, we are using high-density array hybridization to examine the global effects of HIV infection on cellular gene expression. Together, these studies have contributed to a better understanding of the role of IFN and PKR in the host antiviral response and the role of PKR and P58IPK in the control of normal cell growth.